We are broadly interested in the mechanisms of influenza A virus induced disease. We have developed a novel in vivo reporter system with which to label cells that become infected. Importantly, these cells continue to express the reporter even if the virus is eventually cleared from the infected cell. Using this system, we have identified a lung epithelial cell type (club cells) that can become infected, and then clear and survive viral infection. In our preliminary data, we have shown that these cells are highly sensitive to interferon stimulation. Surviving cells also have highly up-regulated expression of chemokines, and that specific depletion or removal of these surviving cells positively influences lung repair after virally induced injury. This proposal will test two major questions: 1) Why are club cells uniquely able to survive direct viral infection (Aim 1) and 2) How are surviving cells influencing lung pathology during viral infection (Aim 2). Aim 1 details experiments designed to understand how club cells are surviving infection by characterizing the nature of the interferon stimulated gene (ISG) response during viral stimulation. We will not only look at the transcriptional and epigenetic factors influencing the increased ISG response, but also define which ISGs are the most important for influencing cellular survival. Aim 2 proposes to study how surviving cells are contributing to viral pathogenesis. We will genetically manipulate surviving cells in vivo to modulate their ability to secrete immunomodulatory factors. We will also directly neutralize the factors secreted by surviving club cells. This is the first description of cells tha can survive acute influenza virus infection, and the experiments in this proposal will increase our understanding of the mechanisms underlying cell survival as well as how these cells contribute to viral pathogenesis. Not only are these important questions for understanding the basic science of how viruses induce disease, but may also provide the basis of novel therapeutic intervention strategies targeting surviving cell populations.